Placental Pathology I: Basics for the OB/GYN

Reading: https://www.contemporaryobgyn.net/view/placental-pathology-it-time-get-serious 

• Great article for this! 

What do we hope to get by sending a placenta to pathology? 

We want to know what happened! 

The goals are to get: 

• Findings that are relevant to the immediate care of the mother or baby

• Findings predictive of possible recurrence that could guide pregnancy care in subsequent pregnancies 

• Diagnoses that explain adverse pregnancy events (probably the most common reason we send a placenta) 

• Findings that may be important in medico-legal investigation of perinatal mortality and long-term morbidity 

So… which placentas should we send? 

There are many reasons, and some of them may depend on your institution, but we have broken this down into three categories 

• Maternal reasons 

  • Preterm delivery

  • Unexpected or recurrent pregnancy complications 

  • Maternal systemic disorders (ie. preeclampsia, malignancy, diabetes, etc) 

  • Infection

  • Excessive third-trimester bleeding 

• Fetal reasons 

  • Stillbirth, neonatal death 

  • Unexpected NICU admission 

  • SGA or LGA 

  • pH <7.0. 5-minute Apgar <7, or birth depression 

  • Neonatal seizures 

  • Hydrops, severe oligo/poly 

  • Multiple gestation 

• Placental reasons 

  • Structural abnormalities or size abnormalities 

  • Possible incomplete placenta 

• We can see that some of these reasons may not present until after the first day of life, so would recommend holding the placenta for up to 7 days if needed (can be stored unfixed in a fridge for that long!) 

The Anatomy and Development of the Placenta 

www.placentalab.org

We are going to first discuss a full-term placenta and then go over embryology

• The placenta can be thought of as three layers:

  • Maternal side (basal plate) 

    • Contains trophoblastic cells and decidual cells and contain the decidua basalis 

    • From the basal plate, the placenta septa bulge into the intervillous space, creating a system of grooves 

    • Basal plate is also penetrated by endometrial arteries and venules 

  • Intervillous space - separates the maternal and fetal side 

    • Exchange between the fetal and maternal circulatory systems occur between the main stem villi and the maternal endometrial arteries and venules in this space 

    • Remember: fetal and maternal blood don’t mix! 

  • Fetal side (chorion plate)  

    • Made of connective tissue and contains the amnion, the main stem villi, and chorionic arteries and veins, which then coalesce at the cord insertion site → umbilical cord 

    • The chorionic arteries and veins → arterioles and venules of the main stem villi 

    • The main stem villi project into the intervillous space and are connected to the maternal basal plate by anchoring villi 

• Placental embryology - super basic 

  • After fertilization and implantation, around day 5, the blastocyst is formed 

  • The blastocyst will eventually implant, and will contain the blastocyst cavity, the inner cell mass, and the trophoblast (which becomes the placenta) 

  • During implantation, there are complex interactions between the endometrium and the embryo → apposition, adhesion, and invasion 

    • Any dysfunction in these 3 processes can lead to abnormal placentation that can lead to affected placental function 

Popular Birthing Trends and the OB/GYN

What are some birthing trends that we have seen rise in the United States?

• Obviously, there are many, but unfortunately, we don’t have time to address all of them, and not all of them have robust scientific literature. Therefore, we will focus on some that are more controversial and may come up more often to help our colleagues navigate these trends with their patients that might desire them. 

• Please see our other episode on limiting interventions in birth to look at some other trends that we fully support, like having a doula or other support person in labor and nonpharmacologic methods for coping. 

• Today, we will discuss: 

  • Lotus Birth 

  • Vaginal seeding 

  • Placentophagy (ie. eating the placenta)

Lotus Birth 

• What is a lotus birth? 

  • Practice of leaving the placenta attached to the umbilical cord and baby until the cord falls off on its own 

  • Anecdotally, this can take up to 3-10 days 

  • Conventional practice, as we know, is for delayed cord clamping for 30-60 seconds 

• What are the perceived benefits? 

  • Modern resurgence is thought to be credited to Claire Lotus Day in 1974 

  • She observed that apes don’t sever their infants from placenta 

  • Delayed cord clamping does have many benefits, as we reviewed in previous episode Delayed Cord Clamping 

    • Increased hemoglobin levels, improved iron stores in first few months of live, increased red blood cell volume, decreased need for blood transfusion, and decreased risk of NEC and IVH 

  • There isn’t a lot of research about the benefits of lotus birth, but those that practice it believe it can: 

    • Increase blood and nourishment from the placenta 

    • Decrease injury to the belly button 

    • Be a gentle, less-invasive transition for the baby to the world 

    • Be a ritual to honor the placenta (though there does not appear to be written record of cultures that leave the cord uncut), and gives patients autonomy on their desires for delivery

  • The way it is done: 

    • The cord is not detached during birth and the placenta is usually kept in a cotton bag with a drawstring that contains herbs or salt to dry and preserve the placenta  

• What are the risks? 

  • Qualitative studies show that many patients who practice lotus birth view the placenta as belonging to the baby and that it is something the baby should release when they are ready. They also discuss it in spiritual and ritualistic terms, but medical benefit and cleanliness were often secondary concerns 

  • Overall, very little data about lotus birth 

    • However, there is currently no evidence regarding effects on cognitive or emotional development of infants or possible benefit

    • There are case reports suggesting potential for infection, such as endocarditis from staphylococcus lugdenensis and omphalitis 

    • No data available regarding late-onset sepsis 

• How should we counsel our patients regarding umbilical cord nonseverance? 

  • First of all, we should always respect the wishes and decision of patients 

  • It is important to review patient’s beliefs and why they desire lotus birth 

  • Discuss current evidence (very little) and society recommendations 

    • Important to realize that right now, there are no formal recommendations available from professional societies.

    • From the American Academy of Pediatrics:

      • Providers should conduct routine assessment and management of ill-appearing neonate 

      • Any placenta and umbilical cord attached to affected child should be immediately removed if child is ill appearing (esp if necrotic tissue is evident) 

      • Tissues should be cultured 

      • Antimicrobial coverage with anaerobic bacteria and vanc may be needed to be included to usual regimens 

  • Ultimately, the biggest risk is infection and patients should be counseled by us and pediatrics about signs of neonatal infection

  • Overall, there does not appear to be significant medical benefit to lotus birth and there are possible risks, but if it is highly desired by your patient, it is not unreasonable to achieve 

  • Things to consider: 

    • Cesarean delivery - it is possible to do lotus birth with cesarean 

    • Postpartum hemorrhage - if there is hemorrhage, in order to save the woman’s life, lotus birth may not be possible 

    • Non-vigorous infant or preterm infant - there is not a lot of data in these cases, but should review with patient that in order for expeditious pediatric evaluation, the cord may need to be clamped and cut

    • Placental pathology (ie. accreta, vasa previa) - lotus birth is likely not possible 

    • Review placenta disposal - placenta should not be flushed down the toilet or buried close to the surface of the ground; if it is buried, then it should be disposed of in a location that adheres to local laws and sanitation guidelines 

    • Be careful of buying placenta bags – not sure what the material is made from, not sure what the herbs that are included are, and realistically, not sure if what is included can actually harm babies

Vaginal Seeding 

• What is vaginal seeding?

  • For babies who are born via C-section, inoculation using cotton gauze or swab with maternal vaginal fluid applied to the newborn’s mouth, nose, and/or skin 

• What are the purported benefits? 

  • Thought is that it can restore the newborn’s microbiome that is more typical of vaginal delivery 

  • Epidemiologic studies show that there is a relationship between cesarean sections and increased risks for various conditions such as allergies 

  • Nonvaginal delivery may be associated wit changes in the infant’s microbiome (though changes do not appear to persist) 

• What are the risks? 

  • Vaginal seeding has potential to transfer pathogens to newborns that are associated with vertical transmission (ie. GBS, HIV, HBV, syphilis, etc) 

  • There are other factors that may be related to initial colonization beyond the mode of delivery (ie. gestational age, transfer via breastfeeding) 

  • Of note, both AAP and ACOG recommend against vaginal seeding outside of research settings: 

    • Families should be counseled regarding the risk of exposure to pathogens that may occur despite negative screening because of possible false negative results or acquisition of the pathogen after the screening is done  

    • Concerns are compounded by increased risk of infections in preterm infants 

• How do I counsel my patient? 

  • Again, it is important to discuss the patient’s beliefs and motivations 

  • We should review that currently, there is no data to suggest that vaginal seeding leads to benefits, but there is data about possible harm 

  • Of course, we can’t control what patients will do when we get home, but would recommend against vaginal seeding per ACOG and AAP 

Placentophagy 

• What is placentophagy? 

  • Eating the placenta, usually prepared by steaming, followed by dehydration and then grinding to a powder and then encapsulated 

  • However, there are also practices of eating the placenta raw, cooked, or blended in liquid extracts

• What are the purported benefits? 

  • For spiritual reasons 

  • Claims that it will increase milk supply or improve energy and decrease postpartum depression, though these results have not been substantiated 

• What are the risks?

  • There are no human studies beyond self-reported surveys regarding benefits 

  • There is literature with evidence of direct neonatal harm involving GBS due to horizontal transmission 

  • Risks include bacterial contamination either from maternal genito-urinary flora or during preparation 

    • Optimal preparation temperatures to eradicate various viruses and bacteria are unknown and there is no industry standard 

• How do I counsel my patients?

  • As always, review the patient’s beliefs and motivations 

  • Discuss the current literature and data with the patient and that we ultimately don’t recommend eating the placenta 

  • If someone really wants to do it: 

    • Review that the placenta should be professional prepped if possible - do not do it at home 

    • The process should ensure that the placental tissue gets to high enough temperatures to kill viruses and bacterias 

    • Really recommend against it if there is infection of certain things that can be vertically transmitted (ie. GBS, HIV, Hep B, etc.) 

    • Monitor yourself and your baby closely - if either one gets sick, please seek professional help 

    • Similarly, if patient begins to have symptoms of PPD, don’t wait for the purported benefits of the placenta to kick in; should seek medical help 

The APGAR Score

What is an APGAR?

• 1952: Dr. Virginia Apgar devised scoring system to assess rapidly clinical status of a newborn to determine if prompt intervention is required to establish breathing.

• Has subsequently stuck, and is reported at 1 minute and 5 minutes after birth for all infants

  • Continued at 5 minute intervals thereafter until 20 minutes for scores under 7.

• The score is eponymous for Dr. Apgar as well as an acronym.

• Each component of the score can receive 0, 1, or 2 points:

  • Appearance (color)

    • 2 points: normal over entire body

    • 1 point: normal except extremities (acrocyanosis)

    • 0 points: cyanotic/pale all over

  • Pulse

    • 2 points: HR >100

    • 1 point: HR < 100

    • 0 points: absent HR

  • Grimace (reflex irritability)

    • 2 points: sneeze, cough, or vigorous cry, active withdrawal of extremities to stimulus

    • 1 point: grimace, weak response to stimulus

    • 0 points: no response to stimulus

  • Activity (muscle tone)

    • 2 points: Active motion

    • 1 point: arms and legs flexed to some degree

    • 0 points: hypotonic, limp

  • Respirations

    • 2 points: Good effort, crying

    • 1 point: Gasping, irregular efforts, hypoventilation

    • 0 points: not breathing

• While the Apgar score is useful for conveying information about the infant status quickly, resuscitation needs to be started before the Apgar calculator intervals.

• The Apgar can be to some degree prognostic – an Apgar of 0 at 10 minutes have very few reports of infants surviving with normal neurologic outcomes, and it’s reasonable to consider discontinuing resuscitative efforts at that point.

• The five minute score is generally considered more useful/prognostic:

  • A score of 7-10 is considered reassuring

  • 4-6 is moderately abnormal

  • Under 4 is abnormal, especially in term and late-preterm infants

Limitations of the Apgar Score

• The score is one moment in time, and is subjective in some components

• Multiple factors can influence the score and make it more “false positive” with low scores, such as:

  • Maternal sedation/anesthesia

  • Congenital malformations or genetic abnormalities

  • Gestational age

• Biochemical disturbances such as fetal acidemia must be quite profound to affect the Apgar score

• A low score doesn’t predict morbidity or mortality for any individual infant, and cannot be used alone to diagnose asphyxia.

  • Cord gases should be obtained to demonstrate poor gas exchange and metabolic acidemia in order to truly diagnose asphyxia.

• Apgars are often continued to be assessed during resuscitation, but these are obviously not equivalent to scores assigned to spontaneously breathing infants

  • There is no standard for reporting Apgars after the start of postnatal resuscitation, because those interventions obviously affect the score. 

  • There are expanded Apgar score forms, where additional information regarding the infant’s resuscitation and response can be recorded to help assess the impact of interventions and the infant’s status in light of these.

    • Essentially like a “code sheet” for neonates

Outcomes after Apgar Scoring

• 1 minute Apgar scores don’t predict outcomes well at all

• 5 minute scores of 0-3 correlate with neonatal mortality in large populations, but are not individually good at predicting neurologic dysfunction for an infant.

  • Low Apgar scores do seem to correlate at population level with increased relative risk of cerebral palsy (20-100x higher risk with 0-3 versus 7-10 score).

  • Most infants with low Apgar scores do not go on to develop neurologic issues or CP.

• ACOG does recommend that a cord gas be sent for any 5 minute Apgar of less than 5, and considering sending placenta to pathology as well. 

• Apgars can also be useful to monitor for quality improvement programs to assess both obstetric and pediatric response and resuscitation.

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Polyhydramnios

Reading:  SMFM Consult Series: #46: Evaluation and management of polyhydramnios 

What is polyhydramnios? 

• Definition 

  • Abnormal increase in amniotic fluid volume 

  • Using ultrasonography, defined: 

    • Single deepest vertical pocket (DVP) of fluid >/= 8 cm or 

    • Amniotic fluid index (AFI) >/= 24 cm 

• Prevalence: can complicate 1-2% of singleton gestations, but it is more common in twin gestations, primarily due to complications of monochorionic placentation 

• Degree of polyhydramnios 

  • AFI of 24.0-29.9 cm or DVP 8-11 cm = mild (65-70% of cases) 

  • AFI of 30.0-34.9 cm or DVP of 12-15 cm = moderate (20% of cases) 

  • AFI of >/= 35 cm or DVP >/16 cm = severe (<15%)

What causes polyhydramnios, and how do we counsel patients? 

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• Most cases are mild and idiopathic 

• When etiology is identified, most commonly due to fetal anomaly or maternal diabetes

  • Most anomalies have to do with swallowing issues 

    • GI obstruction: ie. duodenal atresia, TE fistula, thoracic mass, diaphragmatic hernia  

    • Neuro-muscular: Myotonic dystrophy, arthrogryposis, intracranial anatomy 

    • Craniofacial: cleft lip/palate, micrognathia, neck mass  

  •  Fewer due to excess urine production 

    • Renal/urinary - UPJ obstruction, mesoblastic nephroma, Bartter syndrome 

    • Cardiac (basically lesions that lead to high output cardiac failure as well): cardiac structural anomaly, tachyarrhythmia, sacrococcygeal teratoma, chorioangioma 

    • Osmotic diuresis/Other: maternal diabetes, hydrops, idiopathic 

• What evaluations should be done? 

  • Fetal growth

  • Fetal cardiac anatomy 

  • Placenta for presence of large chorioangiomas 

  • Fetal movement to assess neurological function 

  • Position of hands/feet ot rule out arthrogryposis syndromes 

  • Presence and size of fetal stomach to r/o tracheoesophageal fistula or esophageal atresia 

  • Anatomy of fetal face/palate 

  • Positioning and appearance of fetal neck to r/o obstructing mass 

  • Fetal kidney to assess for UPJ obstruction 

  • Lower spine and pelvis for evidence of sacrococcygeal teratoma 

• How worried should the patient be? 

  • Most mild polyhydramnios is idiopathic or due to T2DM, and only 6-10% risk of fetal anomaly, with 1% of neonatal abnormality 

  • However, with severe poly, there is increased risk of fetal anomaly to as high as 20-40% and even risk of neonatal abnormality of 10% 

  • Therefore, those with severe poly should deliver at tertiary care center due to possibility for fetal anomaly

How do we manage polyhydramnios in pregnancy? 

• Treatment 

  • If the poly is severe enough to cause maternal respiratory compromise, significant discomfort, or preterm labor → this can have underlying etiology 

  • In cases of severe poly that results in maternal respiratory compromise or other discomfort, then amnioreduction can be done 

    • However, the polyhydramnios will usually recur 

  • Indomethacin can decrease fetal urine output 

    • There have been studies looking at women who took indomethacin after amnioreduction to try and decrease reaccumulation and re-amnio 

    • However, preterm infants exposed to indomethacin in utero have decreased neonatal urine output and also elevated serum creatinines 

    • Therefore, indomethacin should not be used for sole purpose of decreasing amniotic fluid in the setting of poly 

• Antepartum management 

  • Many studies have shown that idiopathic poly has been associated with infant birth weight >4000g in 15-30% of cases 

  • Reports of whether perinatal mortality is increased with idiopathic poly have been inconsistent 

    • Currently recommendation from SMFM is that antenatal fetal surveillance is not required for the sole indication of mild idiopathic poly 

    • Similarly, recommendation is that labor should be allowed to occur spontaneously at term for women with mild idiopathic poly, and that induction, if planned, should not occur at <39 weeks of gestation in the absence of other indications 

    • Most of delivery should be determined based on usual obstetric indications 

Monkeypox for the OB/GYN

Reading/sources:

• SMFM statement from 8/16/22: Monkeypox and Pregnancy: What Maternal-Fetal Medicine Subspecialists Need to Know

• Meaney-Delman et al. A Primer on Monkeypox Virus for Obstetrician-Gynecologists. Obstet Gynecol, 2022;00:1-7. DOI: 10.1097/AOG.0000000000004909
  

What is monkeypox and how is it transmitted? 

• Name and type of virus 

  • WHO is planning to rename the virus to reduce stigma and racist overtones - but this hasn’t happened yet! 

  • Orthopoxvirus (genus of Poxviridae family) and has features similar to smallpox or variola 

    • DNA genome

    • There are two different strains: the Congo basin clade and the west African clade 

      • Congo basin clade has historically caused more severe disease and is thought to be more transmissible 

      • The West African clade seems to be the dominant circulating strain → case fatality ratio of 3% to 6% 

• Cases and outbreak 

  • First case was in 1970 in the Democratic Republic of Congo

  • First case in the US in this outbreak was on 5/17/2022 

  • Most recent reports from the CDC states (as of 8/31/2022) - there have been 18,989 total confirmed monkeypox cases in the US 

  • Demographics 

    • There is not complete demographics data for everyone

    • Most recent data from mid August from the CDC shows that only 1.5% of all cases were in women and transgender men

    • No deaths have been reported in this population  

• Transmission 

  • Human to human transmission can occur from

    • Direct contact with infected rash, scab, or body fluid 

    • Respiratory secretions during prolonged or intimate physical contact 

    • Contact with contaminated items, such as clothing or bedding 

  • A person with monkeypox infection is considered contagious from initial viral prodrome and development of rash until lesions have full healed and new skin has formed over the scabs 

  • Unclear if transmission can also occur through vaginal or seminal fluids 

  • Perinatal infection can occur through transplacental transmission or during close contact during and after birth 

  • Zoonotic transmission can also occur following direct contact with blood, bodily fluids, or cutaneous/mucosal lesion of infected animals 

Clinical Presentation 

• Current outbreak 

  • Many of the initial patients in this outbreak have shown painful genital and perianal lesions, oral lesions, and proctitis in the setting of mild or no prodromal symptoms 

• Clinical course 

  • Average time between contact with monkeypox and symptoms is 5-13 days, with range of 4-17 days 

  • Classic features of infection: 

    • Fever, lymphadenopathy, malaise, headache, muscleaches 

    • Can have lymphadenopathy

    • Rash develops approximately 1-4 days after prodromal symptoms → deep-seated vesicular or pustular, often beginning centrally and spreading to the limbs 

    • Rash can last 2-4 weeks, progressing through stages includes macules, papules, vesicles, pustules, and even scabs and crusts 

    • Rash can leave scars

• From the Green Journal article (not sure we can use?) 

Pregnancy Implications of Monkeypox 

• Not very much is known: 

  • We reviewed that the monkeypox virus can be transmitted to the fetus during pregnancy or to the newborn by close contact during and after birth 

  • There has been an increased risk of maternal mortality and morbidity documented with other poxviruses, but it’s unknown if pregnant people are more susceptible to monkeypox or if disease is more severe in pregnancy 

  • One publication looked at 5 cases of documented perinatal outcomes 

    • 2 = SAB 

    • 1 = stillbirth 

    • 1 = preterm birth 

Evaluation for individual with suspected monkeypox 

• Routine screening is not recommended for asymptomatic patients 

• If suspicion of monkeypox virus infection:

  • Collect recent travel history, ask specifically about countries where monkeypox has been reported 

  • If rash or anogenital lesions, ask about close contact or sexual exposure to someone with monkeypox 

  • Full body skin exam, including oral mucosa, genital, and rectal areas, + evaluate lymph nodes 

  • Isolation from others

  • Consultation with infectious disease 

• Diagnosis 

  • Two-step process requiring initial identification of an orthopoxvirus 

  • If orthopoxvirus is confirmed, specimens are sent for monkeypox virus-specific testing 

  • Multiple samples should be collected, ideally from different lesions (2-3 from different areas of the body with diff appearance) for PCR testing 

  • Please follow your own hospital’s guidelines on how to obtain these samples!

  • As there aren’t really any other orthopox viruses in the US, we shouldn’t wait for the confirmatory testing before initiating infection-control procedures and preventative strategies + treatment 

• Healthcare provider precautions 

  • Standard precautions and wear PPE: gown, gloves, eye protection, and N95 mask 

  • Any procedure where there is aerosolization (ie. intubation/extubation), should be done in airborne infection-isolation room 

Treatment 

• Disease is usually self-limited, but disease can progress to severe, so certain populations at risk of severe disease 

  • This includes pregnant patients, people who are breastfeeding, and those with oral, ocular, genital, or anal lesions 

• No specific treatment for monkeypox virus infection

  • However, there are 2 antivirals +immune globulin available 

  • Tecovirimat (Tpoxx) - antiviral (limited to health department/CDC Expanded access protocol) 

    • Approved by FDA for treatment of smallpox virus infection and may prove beneficial for monkeypox 

    • Available in oral and IV formulations 

    • Works by blocking cellular transmission of the virus 

    • Both forms have been used to treat patients during the current outbreak in the US

    • No human data is available during pregnancy, but no fetal toxic effects were observed in mice studies using oral medication 

    • Not known if present in breastmilk 

  •  Cidofovir - antiviral (Off-label use, available for use in outbreak setting) 

    • Approved by the FDA for treatment of CMV retinitis in patients with AIDS 

    • Can be used for orthopoxviruses in an outbreak setting 

    • In animal studies, cidofovir has been associated with embryotoxicity and teratogenicity, but no adequate or well-controlled studies in humans 

  • Brincidofovir - antiviral (availability limited to Strategic National Stockpile distribution) 

    • Approved by FDA to treat smallpox 

    • Unfortunately, in animal studies, there have been embryo-fetal toxicity demonstrated + structural malformations

    • Therefore, alternative therapy is recommended in pregnancy  

  • IVIG - also available in outbreak setting 

    • Also no human data or animal data in pregnancy 

• Prevention 

  • Primary prevention is from isolating from individuals with infection

    • Avoid close contact and sexual activity with people with infection 

  •  Postexposure prophylaxis 

    • CDC has tools to assess the risk of monkeypox virus infection and recommends post-exposure vaccination for specific risk exposures or risk factors 

      • Criteria

        • Within 4 days of known exposure to reduce likelihood of infection or between 4-14 days to reduce severity symptoms 

        • Known contacts of monkeypox cases ID’ed by public health via case investigation 

        • Presumed contacts who meet criteria: 

          • Know that sexual partner in the past 14 days was diagnosed with monkeypox or 

          • Had multiple sexual partners in past 14 days in a jurisdiction with known monkeypox 

    • If given within 4 days of exposure, vaccine is likely to prevent monkey pox virus infection 

    • Of note, there are two types of vaccines 

      • JYNNEOS = live-non-replicated viral vaccine - There are no studies in pregnant patients

        • Pregnancy, however, is not a contraindication to post exposure prophylaxis with vaccination if the individual is otherwise eligible 

      • ACAM2000 - repliating viral vaccine licensed for prevention of smallpox 

        • Contraindicated in pregnant or breastfeeding people due to risk of pregnancy loss, congenital defects, and vaccinia virus infection 

  • Preexposure prophylaxis 

    • Attenuated live-virus vaccine and replication-competent vaccine are available 

    • Routine immunization of all healthcare workers is not currently recommended 

    • Only recommended for those whose jobs may expose them to monkeypox (ie. lab personnel and healthcare workers who administer a replication-competent vaccinia virus vaccine or anticipate caring for many patients with monkeypox)